Recent studies have indicated a pharmacologic elevation of serum high density lipoprotein (HDL) concentrations may be linked to the prevention of atherosclerosis, and subsequently, coronary heart disease. See summary of the second report of the National Cholesterol Education Program (NCEP) Expert Panel on detection, evaluation, and treatment of high blood cholesterol in adults (Adult Treatment Panel II). J.A.M.A. 148:36-69, 1988. Atherosclerosis is one of the leading causes of death in modern societies, and is initiated by lipid, mostly cholesterol, accumulation in the arterial wall. The accumulation triggers a cascade of events, resulting in the formation of an atherosclerotic plaque, and symptomatic atherosclerotic disease. See Wissler, R W: Update on the pathogenesis of atherosclerosis. Am. J. Med. 91: (supp. 1B)3S-9S, 1991, and Ross, R.: The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 362:801-809, 1993. The lipoproteins that transport cholesterol are classified into three major lipoprotein classes in the serum: High density (HDL), low density (LDL) and very low density (VLDL) lipoproteins. The two main subclasses HDL.sub.2 and HDL.sub.3 have been identified within the HDL density range. Further, apoproteins A1 and A2 are the major apoprotein constituents of HDL, and have been considered to be anti-atherogenic due to their abilities to transport cholesterol from arteries to the liver for catabolism and excretion. See Furchart J. and Ailhaud G.: Apoliprotein A-containing lipoprotein particles: Physiological role, quantification and clinical significance. Clin Chem. 38:793-797, 1992. HDL cholesterol is often referred to as "good" cholesterol since the negative association between serum HDL concentration and coronary heart disease is at least as strong as the positive association between low density lipoprotein (LDL) and coronary heart disease.
Management of hyperlipidermias constitutes a major health problem in the United States. A number of useful lipid-lowering (antiatherosclerotic) agents are currently marketed. However, these drugs all suffer from some disadvantage such as, but not limited to, patient non-compliance, production of side effects, or sub-optimal effects on serum cholesterol at tolerated doses. It is believed that none of the currently available drugs was developed to increase HDL-cholesterol and accordingly those with the greatest effects on HDL-cholesterol are capable of elevating this lipoprotein by 10-25%. It will be appreciated that an improved antiatherosclerotic drug designed to substantially elevate serum HDL-cholesterol is desireable. See P. Greenspan, "Drugs Affecting Cholesterol Metabolism," Georgia Pharmacist Quarterly, 70, 1-2, 1993.
It is known that epileptic subjects, treated with anticonvulsants such as phenobarbital and/or phenytoin had higher levels of HDL-cholesterol than matched patients without epilepsy. See Luoma P. Myllyla V and Hokkanen E: Relationship between plasma High-Density Lipoprotein Cholesterol and anticonvulsant levels in epileptics. J. Cardiovascular Pharmacol. 4:1024-1027, 1982. It was speculated that hepatic microsomal enzyme induction may play a role in the elevation of serum HDL levels and thus in the reduction of cholesterol accumulation, since several of the most widely used anticonvulsant drugs are inducers of hepatic mixed function oxidases. Phenobarbital was known to be an inducer of the cytochromes P450, and prospective experiments demonstrated that phenobarbital could elicit increases in total serum HDL cholesterol/total cholesterol ratios. See Luoma P. Marniemi J, and Sotaniemi E.: The effects of phenobarbital on serum high densitylipoprotein subfractions and apolipoproteins. Res. Comm. Chem. Path Pharmacol. 62:125-128,, 1988 and Chao, Y. Pickett, C. Yamin T, Guo L. Alberts A, and Kroon P.: Phenobarbital induces rat liver apolipoprotein A1 mRNA. Molec. Pharmacol 27:394-398, 1984. Phenobarbital was also noted to increase HDL-cholesterol and apoA1 in rats, though the mechanism of this elevation is not yet understood. See Chao, Y. Pickett, C. Yamin T, Guo L. Alberts A, and Kroon P.: Phenobarbital induces rat liver apolipoprotein A1 mRNA. Molec. Pharmacol 27:394-398, 1984.
Based upon the foregoing, it has been found that the elevation of serum HDL-cholesterol levels can be accomplished by the selective induction of hepatic cylochrome P450IIIA (CYP3A) activity. In accordance with the present invention, a family of related compounds have been found to cause a significant elevation of serum HDL cholesterol concentration from 20% to greater than 200%. The family of related compounds are substituted phenylmethanes linked to a heteroaromatic ring containing an unshared pair of electrons in the 3 or 4-N of imidazole or the 4-N of pyridine. The elevation of serum HDL cholesterol levels is accomplished by the selective induction of hepatic cytochrome P450IIIA (CYPA3) activity. Compounds which specifically induce CYPA3 produce significant increases in HDL cholesterol.
Clotrimazole is the lead structure for a series of novel N-substituted imidazoles and related heteroaromatic structures intended to raise HDL cholesterol levels. Triphenylmethyl substituted imidazoles were synthesized by treating the corresponding triphenylmethyl chloride with imidazole or related heteroaromatic compounds. The structure of the compound had a measurable effect on the ability of the compound to increase the rate of CYP3 A activity.
A heteroaromatic nucleus containing basic nitrogen must be present. Significant activity is achieved using substituted imidazoles, 2-methylimidazole or pyridine. The highest activity is associated with the presence of the triphenylmethyl group on N-1 of imidazole. High magnitude CYP3A induction is found in four substituted triphenylmethyl imidazoles: meta-chloro, para-chloro, meta-fluoro and para-fluoro.